Opposing actions of renal tubular- and myeloid-derived porcupine in obstruction-induced kidney fibrosis.
Journal Article (Journal Article)
Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Here, we investigated the tissue-specific contributions of porcupine to renal fibrosis and inflammation in ureteral obstruction using mice with porcupine deletion restricted to the kidney tubular epithelium or infiltrating myeloid cells. Obstruction of the ureter induced the renal mRNA expression of porcupine and downstream targets, β-catenin, T-cell factor, and lymphoid enhancer factor in wild type mice. Renal tubular specific deficiency of porcupine reduced the expression of collagen I and other fibrosis markers in the obstructed kidney. Moreover, kidneys from obstructed mice with tubule-specific porcupine deficiency had reduced macrophage accumulation with attenuated expression of myeloid cytokine and chemokine mRNA. In co-culture with activated macrophages, renal tubular cells from tubular-specific porcupine knockout mice had blunted induction of fibrosis mediators compared with wild type renal tubular cells. In contrast, macrophages from macrophage-specific porcupine deficient mice in co-culture with wild type renal tubular cells had markedly enhanced expression of pro-fibrotic cytokines compared to wild type macrophages. Consequently, porcupine deletion specifically within macrophages augmented renal scar formation following ureteral obstruction. Thus, our experiments suggest a benefit of interrupting Wnt secretion specifically within the kidney epithelium while preserving Wnt O-acylation in infiltrating myeloid cells during renal fibrogenesis.
Full Text
Duke Authors
Cited Authors
- Lu, X; Rudemiller, NP; Ren, J; Wen, Y; Yang, B; Griffiths, R; Privratsky, JR; Madan, B; Virshup, DM; Crowley, SD
Published Date
- December 2019
Published In
Volume / Issue
- 96 / 6
Start / End Page
- 1308 - 1319
PubMed ID
- 31585741
Pubmed Central ID
- PMC6875628
Electronic International Standard Serial Number (EISSN)
- 1523-1755
Digital Object Identifier (DOI)
- 10.1016/j.kint.2019.06.020
Language
- eng
Conference Location
- United States